Since its initial funding through a SCOR grant in 2002, the UCLA Center for Neurovisceral Sciences and Women's Health has pursued the general hypothesis that many functional disorders, including irritable bowel syndrome (IBS) and interstitial cystitis/painful bladder syndrome (IC/PBS), are related to enhanced stress responsiveness, and that the greater prevalence of these syndromes in women is related to sex related differences in responses to perturbations of homeostasis. Building on results generated during the past 2 funding periods, the current proposal aims to apply novel conceptual, technical and analytical tools to address the following interdisciplinary theme, Sex-Related Individual Differences in Central Stress Response Systems and Their Role in IBS Pathophysiology and Treatment Response. We propose to test the general hypothesis that subsets of patients can be identified which are characterized by unique clusters of central and peripheral endophenotypes, and which may show differential responsiveness to treatment. The 3 Projects of the SCOR, supported by two scientific Cores will address two overarching themes: 1) Hypothalamic-Pituitary-Adrenal (HPA) axis and central stress systems, and 2) Endophenotype-based subgrouping of IBS patients. We will address these 2 themes through 3 synergistic, translational research Projects, with an emphasis on sex differences. Project 1 will conduct a comprehensive genetic, molecular and functional phenotyping of the HPA axis in IBS patients and healthy controls establish regional brain CRF/CRF1R expression and delineate engagement of central stress circuits in an animal model of IBS. Project 2 will test the hypothesis that chronic stress in IBS is associated with HPA axis dysregulation, increased visceral adipose tissue (VAT) accumulation and circulating adipokines, which modulate HPA axis responsiveness, and mediate regional brain changes. Project 3 will perform comprehensive endophenotyping using biomarkers collected from all 3 Projects within a large group of IBS patients to identify unique clusters of endophenotypes, and distinguish a subgroup with an upregulated CRF/CRF1R signaling system who can be identified by their responsiveness to a selective CRFIR antagonist.